Activation of PINK1/Parkin-mediated Mitochondrial Quality Control

Target Advancement Program, 2017

Study Rationale:Homeostasis (balance) of mitochondria, the powerhouses of cells, is crucial for longevity. Accumulation of damaged mitochondria is toxic for cells, which is believed to be one of the triggers that leads to neurodegeneration in Parkinson's disease (PD). We plan to investigate the cellular mechanisms of a mitochondrial safeguard, the protein kinase (enzyme that modifies proteins) PINK1. Since PINK1 and Parkin (associated protein) are often mutated in PD, we believe that tuning mitochondrial PINK1 through the intramembrane protease (enzyme that breaks down proteins) PARL, may serve as possible strategy to overcome malfunction in mitochondrial control.

Hypothesis:We will test the hypothesis that reducing PINK1 turnover by applying inhibitors to the mitochondrial protease PARL will provide a neuroprotective effect in PD.

Study Design:This project aims to identify small molecule drugs that inhibit the intramembrane protease PARL and sensitize and activate the PINK1/Parkin pathway to prevent accumulation of mitochondrial damage and neuronal cell death. However, no potent inhibitors for PARL currently exist. Therefore, we aim to set up robust screening approaches and use cell-based and biochemical assays (tests) for PARL activity.

Impact on Diagnosis/Treatment of Parkinson's disease:We anticipate that this project will provide compounds to bock PARL activity.

Next Steps for Development:Identification of the first potent and specific PARL inhibitor will enable follow-up studies in pre-clinical models to define the potential of targeting PARL to treat PD.